Even though numerous drugs and therapeutic agents, etc. for treating diseases have been developed, a problem of penetrating a biological barrier (such as barriers of skin, oral mucosa, and brain blood vessels) and a problem of efficiency in drug delivery still remain as points to be improved.
A drug is generally administered orally in a refined or capsule form. However, numerous drugs cannot be effectively delivered only by the above administration method since the drugs disappear due to being digested or absorbed in a gastrointestinal tract or a mechanism of a liver. Furthermore, some drugs cannot be diffused effectively after penetrating an intestinal mucous membrane. In addition, compliance of a patient also becomes a problem (for example, when a patient needs to take a drug at specific intervals or in case of a critical patient who cannot take a drug).
Another common technology in drug delivery is using a conventional needle. While a method using the conventional needle is effective compared to oral administration, it has a problem of causing pain at an injection site, local damage of skin, disease infection at bleeding and injection sites, etc.
To solve the above problems, various microstructures including a microneedle have been developed. The microneedle developed so far has been mostly used in delivering a drug in a body, collecting blood, detecting a substance to be analyzed in a body, etc. Unlike the conventional needle, the microneedle is characterized by painless skin penetration and no external damage, and a diameter of a top portion of the microneedle for minimal pricking is important in painless skin penetration. In addition, since the microneedle has to penetrate a stratum corneum of 10-20 μm, which is the strongest obstacle in skin, the microneedle needs to have sufficient physical hardness. In addition, a proper length of the microneedle for improving drug delivery efficiency by reaching a capillary vessel should also be considered.
Various types of microneedles were developed after an in-plane type microneedle (Lin Liwei et al., “Silicon-processed Microneedles”, Journal of microelectromechanical systems: a joint IEEE and ASME publication on microstructures, microsensors, and microsystems 8(1): 78-84 (1999)) was previously suggested. A method for fabricating an out-of-plane type solid microneedle (U.S. Patent Application Disclosure No. 2002138049, “Microneedle devices and methods of manufacture and use thereof”) using etching manufactures a solid silicone microneedle with a diameter of 50-100 μm and a length of 500 μm, thus being unable to realize painless skin penetration and having a difficulty in delivering a drug or a cosmetic component to a target site.
Meanwhile, Prausnitz of University of Georgia in the U.S. has suggested a method for fabricating a biodegradable polymer microneedle by etching glass or forming a mold using photolithography (Jung-Hwan Park et al., “Biodegradable polymer microneedles: Fabrication, mechanics and transdermal drug delivery,” Journal of Controlled Release 104(1): 51-66 (2005)). In addition, in 2006, a method for fabricating a biodegradable solid microneedle by mounting a substance fabricated in a capsule form on an end of the mold fabricated by a photolithography method was suggested (Park J H et al., “Polymer Microneedles for Controlled-Release Drug Delivery,” Pharmaceutical Research 23(5): 1008-19 (2006)). When this method is used, a drug that can be fabricated in a capsule form may be freely mounted, but there is a limitation in application to a drug that needs to be administered in a large amount since hardness of a microneedle weakens when an amount of a mounted drug increases.
In 2005, an absorption type microneedle was suggested by Nano Device and Systems Inc. (Japanese Patent Application Disclosure No. 2005154321; and Takaya Miyano et al., “Sugar Micro Needles as Transdermic Drug Delivery System,” Biomedical Microdevices, 7(3): 185-188(2005)). The above absorption type microneedle is to be used in drug delivery or cosmetic care by being inserted in skin and not removed. In this method, a microneedle was fabricated by applying a composition in which maltose is mixed with a drug to a mold and coagulating the composition. The Japanese patent suggests transdermic drug delivery by fabricating the absorption type microneedle, but the microneedle caused pain when penetrating skin. In addition, due to a technical limitation of mold fabrication, it was impossible to fabricate a microneedle that has a proper top portion diameter causing no pain and a length in a range required for effective drug delivery, i.e. a length equal to or greater than 1 mm.
A biodegradable microneedle that was fabricated by Prausnitz of University of Georgia in the U.S. was fabricated in a polydimethylsiloxane (PDMS) mold using a substance in which polyvinylpyrrolidone (PVP) and methacrylic acid (MAA) were mixed (Sean P Sullivan et al., “Minimally Invasive Protein Delivery with Rapidly Dissolving Polymer Microneedles,” Advanced Materials 20(5): 933-938(2008)). In addition, a microneedle was also fabricated by putting carboxymethyl cellulose in a pyramidal mold (Lee J W et al., Dissolving microneedles for transdermal drug delivery, Biomaterials 29(13): 2113-24 (2008)). Despite their advantage of being able to rapidly, easily, and conveniently fabricate a microneedle, the methods using molds have not succeeded in overcoming their limitation of being difficult to fabricate a microneedle with an adjusted diameter and length of the microneedle.
Skin is formed of the stratum corneum (<20 μm), an epidermis (<100 μm), and a dermis (300-2,500 μm). Therefore, to deliver a drug and a skin care component to a specific skin layer without causing pain, fabricating a microneedle to have a diameter of a top portion within 30 μm, an effective length of 200-2,000 μm, and sufficient hardness for skin penetration is effective in delivering the drug and the skin care component. In addition, to deliver a drug or a cosmetic component, etc. through a biodegradable solid microneedle, any process that may destroy activation of the drug or the cosmetic component, such as a high-temperature treatment, an organic solvent treatment, etc., should be avoidable in a process of manufacturing a microneedle.
A method for manufacturing a microstructure using a conventional mold is the most commonly-used manufacture method. However, the manufacture method using the mold has a limitation in which loss occurs in a process of separating the mold. This is due to a damage of a fabricated microstructure which occurs in a process of separating the microstructure from the mold by a contact force between the microstructure manufactured in the mold and the mold. In addition, the method for manufacturing the microstructure using the mold has a limitation of not being able to fabricate a microstructure with a large aspect ratio. This limitation is caused by a difficulty of filling a viscous composition into a micro-mold having a large aspect ratio.
In addition, a method for manufacturing a microstructure by extending a viscous composition through contact with a pillar or a substrate is a fabrication method that is capable of fabricating a structure with a relatively high aspect ratio. However, loss in a process of separating the structure also occurs in this method. In addition, flatness of the pillar or the substrate determines a degree of contact with the viscous composition, which causes a limitation in fabrication yield of a microstructure. That is, due to a difficulty of maintaining the flatness, uniformity and yield of the fabricated microstructure are lowered.
The present inventors have tried to overcome problems of the prior art through completion of the present invention.
Throughout the present specification, several papers and patent documents are used as references, and the citations thereof are indicated. The disclosure of the cited papers and patent documents is incorporated in the present specification by reference in its entirety, to describe a level of a technical field to which the present invention pertains and content of the present invention more clearly.